Genetic Approaches To Characterizing Drug Responses

人类和动物对药物滥用的行为、生理和毒理学反应存在很大的个体差异。这些对药物行为反应的个体差异中，有许多显示了大量的遗传成分。转基因动物为实现几个相互关联的目标提供了手段：1)确定引入或破坏特定基因的生化和行为后果；2)确定在人类研究中确定的候选基因表达过高或过低的后果；3)细胞型特异性表达基因元件的阐明及跨突触基因调控；4)研究不同基因组位点变异间相互作用的影响；5)阐明体内单倍型特异性表达差异水平，特别是当目前可用的培养细胞模型不是最佳的时候。人类等位基因变异和多巴胺系统在奖励、强化和学习机制中的影响导致今年继续关注这些系统。在对联合转运蛋白和转运蛋白/受体敲除的持续研究中，我们已经获得了关于这些基因产物在正常水平下的表达与药物诱导的行为改变之间关系的新数据。在从人类研究中确定的候选基因位点的变异研究中，我们已经确定了可卡因奖励对BDNF和NrCAM表达水平改变的小鼠的显著影响。

There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching several interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes; 2)Ascertainment of the consequences of over- or under-expressing candidate genes identified in human studies; 3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation; 4) Studying influences of interactions between variants at different genomic loci; 5)Elucidating haplotype-specific levels of expression differences in vivo, expecially when currently-available cultured cell models are not optimal. Influences of human allelic variations and dopamine systems in mechanisms of reward, reinforcement and learning have led to continuing focus on these systems during this year. In continuing studies of combined transporter and transporter/receptor knockouts, we have obtained novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In studies of variations at candidate gene loci determined from human studies, we have identified striking effects of cocaine reward in mice with altered levels of expression of BDNF and NrCAM.